Project Summary Influenza A viruses directly cause acute airway inflammation or predispose to secondary bacterial infections. A highly antigenic variability is the main reason for repeated infections. Immune protection induced by current vaccines is closely strain-specific and the vaccines need to be updated each year; the availability of strain-matched vaccines usually lags behind these antigenic changes. Therefore, it is a major goal to broaden the range of influenza vaccine efficacy by using the conserved influenza virus antigens in the hope of inducing cross-protective immunity against both antigenically similar and different viruses. Since influenza virus initiates its infection at respiratory tract, it is important to induce the cross-protective and long-lasting mucosal immunity. However, our ability to safely deliver vaccine antigens across the mucosal barrier for generation of an effective mucosal immunity is very limited, especially for the elderly, young people and pregnant women. We recently found that the mucosal delivery of vaccine antigens by the neonatal Fc Receptor (FcRn) can engender effective immune responses against mucosal infections. These findings lead us to further examine whether FcRn-mediated airway delivery of the influenza antigens induces cross-protective immunity. Therefore, we will intranasally immunize mice and ferret with the conserved influenza antigens that are targeting to FcRn and fully analyze their mucosal and systemic immune responses. Finally, the immunized mice and the ferret will be challenged with virus antigenically similar or dissimilar viruses to evaluate the efficacy of protection or cross protection. The knowledge gained from this study will be important for public health in humans and animals.